Chiral salt resolution

ABSTRACT

A method for resolving enantiomers of a compound containing the structure of the formula:  
                 
 
     wherein R 4  or R 5  may contain one or more asymmetric centers, by mixing a racemic mixture of enantiomers of a compound, containing the structure of said formula; in a solvent, with a resolving compound having a defined stereospecificity, to form a solution and with said resolving agent being capable of binding with at least one but not all of said enantiomers to form a precipitate, containing said at least one of said enantiomers in stereospecific form and collecting either the precipitate and purifying it or collecting the solution with contained other of said enantiomers and recrystallizing the enantiomer contained in said solution.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This non-provisional application claims priority from U.S.provisional application No. 60/294,775, filed May 31, 2001, and U.S.provisional application No. 60/341,048, filed Dec. 6, 2001.

FIELD OF THE INVENTION

[0002] The present invention relates to methods for effecting chiralsalt resolution from racemic mixtures of enantiomers and particularlyprecursor enantiomers used in making pyrrolo[2,3-d]pyrimidine compounds,which are inhibitors of protein kinases. The present invention alsorelates to pyrrolo[2,3-d]pyrimidine compounds and methods of using suchcompounds as inhibitors of protein kinases, such as the enzyme JanusKinase 3.

BACKGROUND OF THE INVENTION

[0003] Pyrrolo[2,3-d]pyrimidine compounds are inhibitors of proteinkinases, such as the enzyme Janus Kinase 3 (JAK3) and are thereforeuseful therapy as immunosuppressive agents for organ transplants, xenotransplation, lupus, multiple sclerosis, rheumatoid arthritis,psoriasis, Type I diabetes and complications from diabetes, cancer,asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerativecolitis, Crohn's disease, Alzheimer's disease, Leukemia and otherindications where immunosuppression would be desirable. Thepyrrolo[2,3-d]pyrimidine compounds, pharmaceutical compositions thereofand methods of use are described in co-pending application Ser. No.09/732,669, filed Dec. 8, 2000, and assigned to the assignee of thepresent invention. The disclosure of said application is included in itsentirety herein by reference thereto. Racemic mixtures of thepyrrolo[2,3-d]pyrimidine compounds are initially obtained whereas theindividual enantiomers in substantially isolated pure form are preferredand at times required for drug use. It is possible to pre-ordain thestereochemistry of the compounds by use of stereospecific precursorcompounds in the sythesis thereof. The methods of the present inventionaccordingly specifically relate to a method for the substantial chiralsalt resolution of racemic mixtures of precursor compounds, used in theproduction of the separate enantiomeric forms of thepyrrolo[2,3-d]pyrimidine compounds.

SUMMARY OF THE INVENTION

[0004] The present invention relates to methods for resolving theenantiomers of the precursors used in preparing a compound of thefollowing formula and particularly the R¹ group thereof:

[0005] or the pharmaceutically acceptable salt thereof; wherein

[0006] R¹ is a group of the formula

[0007] wherein y is 0, 1 or 2;

[0008] R⁴ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynylwherein the alkyl, alkenyl and alkynyl groups are optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₄)alkoxy,(C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano, nitro,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴ is(C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino;

[0009] R⁵ is (C₁-C₉)heterocycloalkyl wherein the heterocycloalkyl groupsmust be substituted by one to five carboxy, cyano, amino, deuterium,hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, (C₁-C₆)acyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; or a group ofthe formula II

[0010] wherein a is 0, 1, 2, 3 or 4;

[0011] b, c, e, f and g are each independently 0 or 1;

[0012] d is 0, 1, 2, or 3;

[0013] X is S(O)_(n) wherein n is 0, 1 or 2; oxygen, carbonyl or—C(=N-cyano)-;

[0014] Y is S(O)_(n) wherein n is 0, 1 or 2; or carbonyl; and

[0015] Z is carbonyl, C(O)O—, C(O)NR— or S(O)_(n) wherein n is 0, 1 or2;

[0016] R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino;

[0017] R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl;

[0018] R² and R³ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substittued by one to threegroups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl.

[0019] The present invention also relates to the production ofstereospecific pharmaceutically acceptable acid addition salts ofcompounds of the formula I. The acids which are used to prepare thepharmaceutically acceptable acid addition salts of the aforementionedbase compounds of this invention are those which form non-toxic acidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,citrate, acid citrate, tartrate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0020] The invention also relates to stereospecific base addition saltsof formula I. The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0021] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight orbranched moieties or combinations thereof.

[0022] The term “alkoxy”, as used herein, includes O-alkyl groupswherein “alkyl” is defined above.

[0023] The term “halo”, as used herein, unless otherwise indicated,includes fluoro, chloro, bromo or iodo. The compounds of this inventionmay contain double bonds. When such bonds are present, the compounds ofthe invention exist as cis and trans configurations and as mixturesthereof. Unless otherwise indicated, the alkyl and alkenyl groupsreferred to herein, as well as the alkyl moieties of other groupsreferred to herein (e.g., alkoxy), may be linear or branched, and theymay also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl) or be linear or branched and contain cyclicmoieties. Unless otherwise indicated, halogen includes fluorine,chlorine, bromine, and iodine.

[0024] (C₂-C₉)Heterocycloalkyl when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

[0025] (C₂-C₉)Heteroaryl when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a Sp³hybridized nitrogen heteroatom.

[0026] (C₆-C₁₀)aryl when used herein refers to phenyl or naphthyl.

[0027] The compounds used in this invention include all conformationalisomers (e.g., cis and trans isomers. The compounds used in presentinvention have asymmetric centers and are therefore chiral and exist indifferent enantiomeric and diastereomeric forms. This invention relatesto the resolution of optical isomers and stereoisomers of the precursorsof constituents and thereby compounds of the present invention, andmixtures thereof, and to all pharmaceutical compositions and methods oftreatment that may employ or contain them. In this regard, the inventionincludes both the E and Z configurations. The compounds of formula I mayalso exist as tautomers. This invention relates to such tautomers andmixtures thereof. In particular, resolution of racemic mixtures ofenantiomers of compounds, used in providing the R¹ substituent offormula I, is effected by treating the racemic mixture with a specificoptical isomer of a disubstituted tartaric acid or tartrate in anappropriate solvent such as ethanol with or without water as aco-solvent. Resolution in obtaining the desired enantiomer in excess of90% is possible in accordance with the method of the present inventionwith the use of resolving agents such as the optical isomers of tartaricacid and tartaric acid derivatives such as di-p-toluoyl-L-tartaric acidand (S)-(+)-Andeno acid (pencyphos,(S)-(+)-2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxyphosphorinane-2-oxide)salt.

[0028] Interaction between antipodes of the resolving material andspecific enantiomer provides a resolution of the racemic mixture wherebya precipitate of the resolving material and enantiomer provides one ofthe desired stereospecific materials and wherein the remainingenantiometer in solution can be separately isolated thereby. Thus,depending on the specific enantiomer desired and the separation methodto be used (i.e., from precipitate or solution), the stereospecificnature of the resolving nature can be concomitantly selected; e.g. an“L” form of the resolving agent such as a tartrate derivative provides aprecipitate of an ‘R’ form of the R¹ substituent and a solutioncontaining the “L” form and vice versa.

[0029] The aforementioned resolving agents are effective in providing a3R,4R enantiomer of the compound of the formula (either in precipitateor solution, as described):

[0030] In accordance with the present invention the method of resolutionof the compound of formula III is effected by the steps of:

[0031] a) mixing a racemic mixture of the compound of formula III in anappropriate solution with a resolving compound, having a definedstereospecificity, for a time sufficient to allow substantialprecipitation of a stereospecific isomer of the racemic mixture from thesolution;

[0032] b) depending on the stereospecific form of the compound which isdesired, collecting either the precipitate and purifying it orcollecting the mother liquor and recrystallizing the enantiomercontained therein.

[0033] With some materials a slurry rather that a solution is formedwith the resolution of the present invention involving a slurry toslurry conversion. The term “solution” encompasses both a solution and aslurry.

[0034] The temperature at which the resolution and precipitation iseffected is preferably ambient temperature and while precipitation timeis not restricted for efficicency the time is preferably no more thanabout four hours. In order to facilitate the resolution it is desirableto use enantiomers in the racemic mixture which are in a stable form andthe compound of formula II is most stable in acid addition salt formsuch as a hydrochloride salt, rather than a free base form and it ispreferred that the racemic compound mixture be accordingly convertedprior to resolution. Thus, for example, formation of the hydrochloridesalt of the compound of formula II is effected preferably in ethanolwith a small amount of toluene as cosolvent. Alternatively, methanol,isopropanol, acetonitrile, or tetrahydrofuran (or mixtures thereof withor without water as a cosolvent) with cosolvents of toluene,ethylacetate, dichloromethane, dichloroethane, or tetrahydrofuran may beused in the salt formation. The HCl salt is particularly preferred sincethis form provides a superior purification and enriched of otherstereomers from the prior step.

[0035] A preferred displacement solvent to be used in the resolution isethyl acetate. Toluene, acetonitrile, or heptanes are also useful assolvents.

[0036] A preferred isolation solvent is acetone. Other solvents usefulin this regard include isopropanol, ethanol, methyl ethyl ketone, methylisopropyl ketone, acetonitrile, and tetrahydrofuran. The solvents mayalso be used as co-solvents with each other or with water.

[0037] Preferred resolution compounds include tartaric acid and itsderivatives such as toluoyl and benzoyl tartaric acids in stereospecificconformation, as described. Other resolution compounds includespereospecific adeno acid and derivatives thereof.

[0038] To facilitate precipitation and recrystalization addition ofseeds is optional, but preferred in order to obtain higher ee materialwith fewer recrystalizations.

[0039] In order to illustrate the procedure and efficacy of the presentinvention the following examples are presented. It is understood thatsuch examples are details contained therein are not to be construed aslimitations on the present invention.

[0040] The present invention also relates to a method for preparing thecompound of the formula

[0041] or the pharmaceutically acceptable salt thereof; wherein

[0042] R¹ is a group of the formula

[0043] wherein y is 0, 1 or 2;

[0044] R⁴ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynylwherein the alkyl, alkenyl and alkynyl groups are optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₄)alkoxy,(C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano, nitro,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴ is(C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino;

[0045] R⁵ is (C₁-C₉)heterocycloalkyl wherein the heterocycloalkyl groupsmust be substituted by one to five carboxy, cyano, amino, deuterium,hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, (C₁-C₆)acyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; or a group ofthe formula II

[0046] wherein a is 0, 1, 2, 3 or 4;

[0047] b, c, e, f and g are each independently 0 or 1;

[0048] d is 0, 1, 2, or 3;

[0049] X is S(O)_(n) wherein n is 0, 1 or 2; oxygen, carbonyl or—C(=N-cyano)-;

[0050] Y is S(O)_(n) wherein n is 0, 1 or 2; or carbonyl; and

[0051] Z is carbonyl, C(O)O—, C(O)NR— or S(O), wherein n is 0, 1 or 2;

[0052] R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino;

[0053] R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl;

[0054] R² and R³ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substittued by one to threegroups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH-(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl;

[0055] said method comprising the steps of:

[0056] a) mixing a racemic mixture of enantiomeric compounds of theformula

[0057] wherein y, R⁴ and R⁵ are as defined above, in a solvent, with aresolving compound having a defined stereospecificity, to form asolution and with said resolving agent being capable of binding with atleast one but not all of said enantiomers to form a precipitate,containing said at least one of said enantiomers,

[0058] b) allowing the mixture to stand for a time sufficient to allowsubstantial precipitation of a stereospecific enantiomer of the racemicmixture from the solution and wherein another of said enantiomersremains in said solution;

[0059] c) depending on the stereospecific enantiomer of the compoundwhich is desired, collecting either the precipitate and purifying it orcollecting the solution with contained other of said enantiomers andrecrystallizing the enantiomer contained in said solution; and

[0060] d) reacting the desired stereospecific enantiomer so formed witha compound of the formula

[0061] wherein R is hydrogen or a protecting group and R² and R³ are asdefined above.

[0062] The present invention also relates to a compound of the formula

[0063] wherein R² and R³ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substittued by one to threegroups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH-(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl.

[0064] The present invention also relates to specifically preferredcompounds selected from the group consisting of:

[0065]Methyl-[(3R,4R)₄-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;

[0066](3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methyl ester;

[0067] 3,3,3-Trifluoro-1(3R,4R)₄-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)propan-1-one;

[0068](3R,4R)₄-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid dimethylamide;

[0069]{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-aceticacid ethyl ester;

[0070]3(3R,4R)₄-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)₃-oxo-propionitrile;

[0071]3,3,3-Trifluoro-1-{(3R,4R)₄-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;

[0072]1-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-but-3-yn-1-one;

[0073]1-{(3R,4R)-3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]4-methyl-piperidin-1-yl}-propan-1-one;

[0074]1-{(3R,4R)-3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;

[0075](3R,4R)-N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-N′-propyl-piperidine-1-carboxamidine;and

[0076] (3R,4R)-N-cyano-4,N′,N′-Trimethyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxamidine.

[0077] The present invention also relates to a pharmaceuticalcomposition for (a) treating or preventing a disorder or conditionselected from organ transplant rejection, xeno transplation, lupus,multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes andcomplications from diabetes, cancer, asthma, atopic dermatitis,autoimmune thyroid disorders, ulcerative colitis, Crohn's disease,Alzheimer's disease, Leukemia, and other autoimmune diseases or (b) theinhibition of protein kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising an amount of an above describedspecifically preferred compound or a pharmaceutically acceptable saltthereof, effective in such disorders or conditions and apharmaceutically acceptable carrier.

[0078] The present invention also relates to a method for the inhibitionof protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising administering to said mammal an effectiveamount of an above described specifically preferred compound or apharmaceutically acceptable salt thereof.

[0079] The present invention also relates to a method for treating orpreventing a disorder or condition selected from organ transplantrejection, xeno transplation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, andother autoimmune diseases in a mammal, including a human, comprisingadministering to said mammal an amount of an above describedspecifically preferred compound or a pharmaceutically acceptable saltthereof, effective in treating such a condition.

[0080] The present invention also relates to a compound of the formula

[0081] The present invention also relates to a compound of the formula

[0082] The present invention also relates to a compound of the formula

DETAILED DESCRIPTION OF THE INVENTION

[0083] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R², R³,R⁴ and R⁵ in the reaction Schemes and the discussion that follow aredefined as above.

[0084] In reaction 1 of Preparation A, the4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI, wherein R ishydrogen or a protecting group such as benzenesulfonyl or benzyl, isconverted to the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound offormula XX, wherein Y is chloro, bromo or iodo, by reacting XXI withN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. Thereaction mixture is heated to reflux, in chloroform, for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.Alternatively, in reaction 1 of Preparation A, the4-chloropyrrolo[2,3-d]pyrimidine of formula XXI, wherein R is hydrogen,is converted to the corresponding4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y isnitro, by reacting XXI with nitric acid in sulfuric acid at atemperature between about −10° C. to about 10° C., preferably about 0°C., for a time period between about 5 minutes to about 15 minutes,preferably about 10 minutes. The compound of formula XXI, wherein Y isnitro, is converted to the corresponding4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of the formula XX, wherein Y isamino, by reacting XXI under a variety of conditions known to oneskilled in the art such as palladium hydrogenolysis or tin(IV)chlorideand hydrochloric acid.

[0085] In reaction 2 of Preparation A, the4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, whereinR is hydrogen, is converted to the corresponding compound of formulaXIX, wherein R² is (C₁-C₆)alkyl or benzyl, by treating XX withN-butyllithium, at a temperature of about −78° C., and reacting thedianion intermediate so formed with an alkylhalide or benzylhalide at atemperature between about −78° C. to room temperature, preferably roomtemperature. Alternatively, the dianion so formed is reacted withmolecular oxygen to form the corresponding4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX,wherein R² is hydroxy. The compound of formula XX, wherein Y is bromineor iodine and R is benzenesulfonate, is converted to the compound offormula XIX, wherein R² is (C₆-C₁₂)aryl or vinyl, by treating XX withN-butyllithium, at a temperature of about −78° C., followed by theaddition of zinc chloride, at a temperature of about −78° C. Thecorresponding organo zinc intermediate so formed is then reacted witharyliodide or vinyl iodide in the presence of a catalytic quantity ofpalladium. The reaction mixture is stirred at a temperature betweenabout 50° C. to about 80° C., preferably about 70° C., for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.

[0086] In reaction 3 of Preparation A, the compound of formula XIX isconverted to the corresponding compound of formula XVI by treating XIXwith N-butyllithium, lithium diisopropylamine or sodium hydride, at atemperature of about −78° C., in the presence of a polar aproticsolvent, such as tetrahydrofuran. The anionic intermediate so formed isfurther reacted with (a) alkylhalide or benzylhalide, at a temperaturebetween about −78° C. to room temperature, preferably −78° C., when R³is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature betweenabout −78° C. to room temperature, preferably −78° C., when R³ isalkoxy; and (c) zinc chloride, at a temperature between about −78° C. toroom temperature, preferably −78° C., and the corresponding organozincintermediate so formed is then reacted with aryliodide or vinyl iodidein the presence of a catalytic quantity of palladium. The resultingreaction mixture is stirred at a temperature between about 50° C. toabout 80° C., preferably about 70° C., for a time period between about 1hour to about 3 hours, preferably about 1 hour. Alternatively, the anionso formed is reacted with molecular oxygen to form the corresponding4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI,wherein R³ is hydroxy.

[0087] In reaction 1 of Preparation B, the4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI is converted tothe corresponding compound of formula XXII, according to the proceduredescribed above in reaction 3 of Preparation A.

[0088] In reaction 2 of Preparation B, the compound of formula XXII isconverted to the corresponding compound of formula XVI, according to theprocedures described above in reactions 1 and 2 of Preparation A.

[0089] In reaction 1 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XVII is converted to the corresponding compound offormula XVI, wherein R is benzenesulfonyl or benzyl, by treating XVIIwith benzenesulfonyl chloride, benzylchloride or benzylbromide in thepresence of a base, such as sodium hydride or potassium carbonate, and apolar aprotic solvent, such as dimethylformamide or tetrahydrofuran. Thereaction mixture is stirred at a temperature between about 0° C. toabout 70° C., preferably about 30° C., for a time period between about 1hour to about 3 hours, preferably about 2 hours.

[0090] In reaction 2 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XVI is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVIwith an amine of the formula HNR⁴R⁵. The reaction is carried out inwater or an alcohol solvent, such as tert-butanol, methanol or ethanol,or other high boiling organic solvents, such as dimethylformamide,triethylamine, 1,4-dioxane or 1,2-dichloroethane, at a temperaturebetween about 60° C. to about 120° C., preferably about 80° C. Typicalreaction times are between about 2 hours to about 100 hours, preferablyabout 48 hours. When R⁵ is a nitrogen containing heterocycloalkyl group,each nitrogen must be protected by a protecting group, such a benzyl.Removal of the R⁵ protecting group is carried out under conditionsappropriate for that particular protecting group in use which will notaffect the R protecting group on the pyrrolo[2,3-d]pyrimidine ring.Removal of the R⁵ protecting group, when benzyl, is carried out in analcohol solvent, such as ethanol, in the present of hydrogen and acatalyst, such as palladium hydroxide on carbon, at temperatures rangingfrom room temperature to about 70° C. The R⁵ nitrogen containinghetrocycloalkyl group so formed may be further reacted with a variety ofdifferent electrophiles of formula II. For urea formation, electrophilesof formula II such as isocyanates, carbamates and carbamoyl chloridesare reacted with the R⁵ nitrogen of the heteroalkyl group in a solvent,such as acetonitrile or dimethylformamide, in the presence of a base,such as sodium or potassium carbonate, at a temperature between about20° C. to about 100° C. for a time period between about 24 hours toabout 72 hours. For amide and sulfonamide formation, electrophiles offormula II, such as acylchlorides and sulfonyl chlorides, are reactedwith the R⁵ nitrogen of the heteroalkyl group in a solvent such asmethylene chloride in the presence of a base such as pyridine at ambienttemperatures for a time period between about 12 hours to about 24 hours.Amide formation may also be carried out by reacting a carboxylic acidwith the heteroalkyl group in the presence of a carbodiimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such asmethylene chloride at ambient temperatures for about 12 to about 24hours, or with an activated ester, such as N-hydroxysuccinimide ester,or 4-nitrophenyl ester in a solvent such as methylene chloride,tetrahydrofuran or ethanol. For alkyl formation, electrophiles offormula II, such as α,β-unsaturated amides, acids, nitriles, esters, andα-halo amides, are reacted with the R⁵ nitrogen of the heteroalkyl groupin a solvent such as methanol at ambient temperatures for a time periodbetween about 12 hours to about 18 hours. Alkyl formation may also becarried out by reacting aldehydes with the heteroalkyl group in thepresence of a reducing agent, such as sodium cyanoborohydride, in asolvent, such as methanol, at ambient temperature for a time periodbetween about 12 hours to about 18 hours.

[0091] In reaction 3 of Scheme 1, removal of the protecting group fromthe compound of formula XV, wherein R is benzenesulfonyl, to give thecorresponding compound of formula I, is carried out by treating XV withan alkali base, such as sodium hydroxide or potassium hydroxide, in analcohol solvent, such as methanol or ethanol, or mixed solvents, such asalcohol/tetrahydrofuran or alcohol/water. The reaction is carried out atroom temperature for a time period between about 15 minutes to about 1hour, preferably 30 minutes. Removal of the protecting group from thecompound of formula XV, wherein R is benzyl, is conducted by treating XVwith sodium in ammonia at a temperature of about −78° C. for a timeperiod between about 15 minutes to about 1 hour.

[0092] In reaction 1 of Scheme 2, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XX is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XXIV, according tothe procedure described above in reaction 2 of Scheme 1.

[0093] In reaction 2 of Scheme 2, the4-amino-5-halopyrrolo[2,3-d]pyrimidine compound of formula XXIV, whereinR is benzenesulfonate and Z is bromine or iodine, is converted to thecorresponding compound of formula XXIII by reacting XXIV with (a)arylboronic acid, when R² is aryl, in an aprotic solvent, suchtetrahydrofuran or dioxane, in the presence of a catalytic quantity ofpalladium (0) at a temperature between about 50° C. to about 100° C.,preferably about 70° C., for a time period between about 2 hours toabout 48 hours, preferably about 12 hours; (b) alkynes, when R² isalkynyl, in the presence of a catalytic quantity of copper (I) iodideand palladium (0), and a polar solvent, such as dimethylformamide, atroom temperature, for a time period between about 1 hour to about 5hours, preferably about 3 hours; and (c) alkenes or styrenes, when R² isvinyl or styrenyl, in the presence of a catalytic quantity of palladiumin dimethylformamide, dioxane or tetrahydrofuran, at a temperaturebetween about 80° C. to about 100° C., preferably about 100° C., for atime period between about 2 hours to about 48 hours, preferably about 48hours.

[0094] In reaction 3 of Scheme 2, the compound of formula XXIII isconverted to the corresponding compound of formula XV, according to theprocedure described above in reaction 3 of Preparation A.

[0095] In reaction 1 of Scheme 3, the compound of formula XVII isconverted to the corresponding compound of formula I, according to theprocedure described above in reaction 2 of Scheme 1.

[0096] The compounds of the present invention that are basic in natureare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent medium or in a suitable organic solvent, such as acetone,methanol or ethanol. Upon careful evaporation of the solvent, thedesired solid salt is readily obtained. The desired acid salt can alsobe precipitated from a solution of the free base in an organic solventby adding to the solution an appropriate mineral or organic acid.

[0097] Those compounds of the present invention that are acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the calcium, sodium andpotassium salts. These salts are all prepared by conventionaltechniques. The chemical bases which are uset as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

[0098] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

[0099] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e, lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (g., lecithin or acacia); non-aqueous vehicles (e.g.,almond oil, oily esters or ethyl alcohol); and preservatives (e.g.,methyl or propyl p-hydroxybenzoates or sorbic acid).

[0100] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0101] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use. The activecompounds of the invention may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0102] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0103] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

[0104] Aerosol formulations for treatment of the conditions referred toabove (e, asthma) in the average adult human are preferably arranged sothat each metered dose or ‘puff’ of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 0.1 mg to 1000 mg. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

[0105] A compound of formula (I) administered in a pharmaceuticallyacceptable form either alone or in combination with one or moreadditional agents which modulate a mammlian immune system or withantiinflammatory agents, agents which may include but are not limited tocyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®, azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3(e.g. Orthocolone®), AtGam, aspirin, acctaminophen, ibuprofen, naproxen,piroxicam, and antiinflmmatory steroids (e.g. prednisolone ordexamethasone); and such agents may be administered as part of the sameor separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

[0106] FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg bodyweight, every 12 hours, within first 48 hours postoperative. Does ismonitored by serum Tacrolimus trough levels.

[0107] Cyclosporin A (Sandimmune oral or intravenous formulation, orNeoral®, oral solution or capsules) is given orally at 5 mg/kg bodyweight, every 12 hours within 48 hours postoperative. Dose is monitoredby blood Cyclosporin A trough levels.

[0108] The active agents can be formulated for sustained deliveryaccording to methods well known to those of ordinary skill in the art.Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214,4,060,598, 4,173,626, 3,119,742, and 3,492,397.

[0109] The ability of the compounds of formula I or theirpharmaceutically acceptable salts to inhibit Janus Kinase 3 and,consequently, demonstrate their effectiveness for treating disorders orconditions characterized by Janus Kinase 3 is shown by the following invitro assay tests.

Biological Assay JAK3 (JH1:GST) Enzymatic Assay

[0110] The JAK3 kinase assay utilizes a protein expressed inbaculovirus-infected SF9 cells (a fusion protein of GST and thecatalytic domain of human JAK3) purified by affinity chromatography onglutathione-Sepaharose. The substrate for the reaction is poly-Glutamicacid-Tyrosine (PGT (4:1), Sigma catalog # PO₂₇₅), coated onto Nunc MaxiSorp plates at 100 μg/ml overnight at 37° C. The morning after coating,the plates are washed three times and JAK3 is added to the wellscontaining 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24mM MgCl2)+0.2 uM ATP+1 mM Na orthovanadate.) The reaction proceeds for30 minutes at room temperature and the plates is washed three moretimes. The level of phosphorylated tyrosine in a given well isquantitated by standard ELISA assay utilizing an anti-phosphotyrosineantibody (ICN PY20, cat. #69-151-1).

Inhibition of Human IL-2 Dependent T-Cell Blast Proliferation

[0111] This screen measures the inhibitory effect of compounds on IL-2dependent T-Cell blast proliferation in vitro. Since signaling throughthe IL-2 receptor requires JAK-3, cell active inhibitors of JAK-3 shouldinhibit IL-2 dependent T-Cell blast proliferation.

[0112] The cells for this assay are isolated from fresh human blood.After separation of the mononuclear cells using AccuspinSystem-Histopaque-1077 (Sigma # A7054), primary human T-Cells areisolated by negative selection using Lympho-Kwik T (One Lambda, Inc.,Cat # LK-50T). T-Cells are cultured at 1-2×10⁶/ml in Media (RPMI+10%heat-inactivated fetal calf serum (Hyclone Cat # A-1111-L)+1%Penicillin/Streptomycin (Gibco)) and induce to proliferate by theaddition of 10 ug/ml PHA (Murex Diagnostics, Cat # HA 16). After 3 daysat 37° C. in 5% CO₂, cells are washed 3 times in Media, resuspended to adensity of 1-2×10⁶ cells/ml in Media plus 100 Units/ml of humanrecombinant IL-2 (R&D Systems, Cat # 202-IL). After 1 week the cells areIL-2 dependent and can be maintained for up to 3 weeks by feeding twiceweekly with equal volumes of Media +100 Units/ml of IL-2.

[0113] To assay for a test compounds ability to inhibit IL-2 dependentT-Cell proliferation, IL-2 dependent cells are washed 3 times,resuspended in media and then plated (50,000 cells/well/0.1 ml) in aFlat-bottom 96-well microtiter plate (Falcon # 353075). From a 10 mMstock of test compound in DMSO, serial 2-fold dilutions of compound areadded in triplicate wells starting at 10 uM. After one hour, 10 Units/mlof IL-2 is added to each test well. Plates are then incubated at 37° C.,5% CO₂ for 72 hours. Plates are then pulsed with ³H-thymidine (0.5uCi/well) (NEN Cat # NET-027A), and incubated an additional 18 hours.Culture plates are then harvested with a 96-well plate harvester and theamount of ³H-thymidine incorporated into proliferating cells isdetermined by counting on a Packard Top Count scintillation counter.Data is analyzed by plotting the % inhibition of proliferation versesthe concentration of test compound. An IC₅₀ value (uM) is determinedfrom this plot.

[0114] The following Examples illustrate the preparation of thecompounds of the present invention but it is not limited to the detailsthereof. Melting points are uncorrected. NMR data are reported in partsper million (δ) and are referenced to the deuterium lock signal from thesample solvent (deuteriochloroform unless otherwise specified).Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. LowResolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard59890, utilizing chemical ionization (ammonium), or a Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) platform whichuses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as theionizing agent. Room or ambient temperature refers to 20-25° C.

EXAMPLE 1 Stable Salt Formation(1-benzyl-4-methylpiperidin-3-yl)-methylamine bishydrochloride

[0115] To a solution of 23.4 kg of(1-benzyl-4-methylpiperidin-3-yl)-methylamine in 10 liters of tolueneand 120 liters of ethanol at 3° C. was added 25 liters of 32% HCl inwater, keeping the reaction temperature below 10° C. 100 liters ofsolvent was distilled off under partial vacuum, and 215 liters of ethylacetate was added at 30° C. 210 liters of solvent was distilled offunder partial vacuum, and a second 215 liters of ethyl acetate was addedand another 210 liters of solvent was distilled off under partialvacuum. 111 liters of acetone was added at 35 C°, the suspension wascooled to 0° C., and then the product,(1-benzyl-4-methylpiperidin-3-yl)-methylamine bishydrochloride, wasfiltered off and washed with 55 liters of acetone. The wet-cake wasreslurried 3 times in ethanol (10 volume equivalents at reflux) toupgrade the diasteromeric ratio of cis:trans from 91:9 to greater than97:3. Total recovery was 19.4 kg, 62% yield. ¹H NMR (CD₃OD, 400 MHz):7.55 (m, 5H), 4.88 (s, 3H), 4.52 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.8 Hz,1H), 3.76 (m, 1H), 3.67 (m, 1H), 3.40-3.00 (m, 3H), 2.78 (3, 3H), 2.55(m, 1H), 2.14 (m, 1H), 1.90 (m, 1H), 1.16 (d, J=7.2 Hz, 3H)

EXAMPLE 2 Resolutionbis[(1-benzyl-4-methylpiperidin-3-yl)-methylamine]di-p-toluyl-L-tartrate

[0116] To a solution of 9.5 kg of(1-benzyl-4-methylpiperidin-3-yl)-methylamine bishydrochloride in 16liters of water was added 33 liters of 2N sodium hydroxide. Solidsprecipitated from the mixture. The slurry was diluted with 43 liters ofisopropanol and 11 liters of methanol to redissolve the solids.Di-p-toluyl-L-tartaric acid (6.3 kg) was added, with precipitation ofsolids. The slurry was heated to reflux to redissolve the solids, thenslowly cooled to 72° C. Seeds ofbis[(1-benzyl-4-methylpiperidin-3-yl)-methylamine]di-p-toluyl-L-tartratewere added (180 grams), and the hazy solution was slowly cooled to 15°C. The solids were filtered and washed with isopropanol to yield 5.9 kgof bis[(1-benzyl-4-methylpiperidin-3-yl)-methylamine]di-p-toluyl-L-tartrate in 44% yield. ¹H NMR (CD₃OD, 400 MHz): 8.04 (d,J=8.4 Hz, 2H), 7.30 (m, 7H), 5.86 (s, 1H), 4.91 (s, 3H), 3.64 (d, J=12.8Hz, 1H), 3.41 (d, J=12.8 Hz, 1H), 3.09 (s, 1H), 2.90 (m, 2H), 2.40 (s,3H), 2.22 (m, 2H), 1.92 (m, 1H), 1.57 (m, 2H), 1.03 (d, J=7.2 Hz, 3H)

EXAMPLE 3 Phencyphos Resolution

[0117] To a solution of 6.83 grams (31.3 mmol) in 250 ml IPA and 10 mlwater was added 7.57 g (+) phencyphos (31.3 mmol), and the mixture washeated to reflux in order to obtain a clear solution. At a temperatureof approximately 65° C. seeding crystals with an ee of 90% were added.Crystallization started within one hour and the mixture was allowed toreach room temperature overnight. Isolation afforded 6.85 g (47%) withan ee of 99%. The filtrate was concentrated, TBME, water and K₂CO₃ wereadded, and the layers separated. The organic layer was dried (Na₂SO₄))and the solvent evaporated. The resulting oil (3.99 grams) was dissolvedin 200 ml IPA and 10 ml water and 4.4 grams(−) phencyphos was added. Themixture was heated to reflux and allowed to cool to room temperatureovernight. This afforded 6 grams (41%) salt with an ee of 99.9+%Analyses were performed on the free amine. The free amine was obtainedby treatment of the salt with TBME, water and K₂CO₃.

[0118] The following schematically illustrate the methods of Examples 1to 3 (wherein Bn is defined as benzyl (—CH₂—C₆H₅)):

EXAMPLE 4

[0119] A racemic mixture of the compound of formula III was resolved:

[0120] Sample Processing:

[0121] A compound of formula III was filtered through a 0.2 um nylon 66filter disc.

[0122] Procedure: (96% Ethanol 4% Water as Solvent)

[0123] 0.8711 grams of the compound of formula III, of the filtrate, wasdissolved in 5.0 ml of a 96:4 ratio of ethanol/water. 1.544 grams ofdi-p-toluoyl-L-tartaric acid was added and the mixture was stirred toobtain a clear solution. The solution was allowed to stand at roomtemperature for approximately 4 hours. The resulting slurry was filteredonto Whatman #2 filter paper and washed with 4.0 ml of a 96:4 ratio ofethanol/water. The solids were air dried to give 0.488 grams of thediastereomer salt.

[0124] 0.488 grams of the diastereomer salt was suspended in 50 ml ofwater then 50 ml of methylene chloride was added. The pH of the mixturewas adjusted to approximately 9 using saturated sodium bicarbonatefollowed by 1.0N sodium hydroxide. Upon completion of the pH adjustment,the layers were separated and the methylene chloride layer was filteredthrough Whatman #2 filter paper. Solvents were then removed by reducedpressure evaporation to give a light orange colored oil. Weight notdetermined. This oil was evaluated by gas chromatography.

[0125] Analytical assay: 97.3% desired enantiomer by normalized areapercent.

EXAMPLE 5

[0126] Procedure: (100% Ethanol as Solvent)

[0127] 0.8714 grams of (1-benzyl-4-methyl-piperidin-3-yl)-methyl-aminewas dissolved in 5.0 ml of 200 proof ethanol. 1.544 grams ofdi-p-toluoyl-L-tartaric acid was added and the mixture was stirred toobtain a clear solution. The solution was allowed to stand at roomtemperature for approximately 4 hours. The resulting slurry was filteredonto. Whatman #2 filter paper and washed with 4.0 ml of a 96:4 ratio ofethanol/water. The solids were air dried to give 0.628 grams of thediastereomer salt.

[0128] 0.628 grams of the diastereomer salt was suspended in 50 ml ofwater then 50 ml of methylene chloride was added. The pH of the mixturewas adjusted to approximately 9 using saturated sodium bicarbonatefollowed by 0.1N sodium hydroxide. Upon completion of the pH adjustment,the layers were separated and the methylene chloride layer was filteredthrough Whatman #2 filter paper. Solvents were then removed by reducedpressure evaporation to give a light yellow colored oil. Weight notdetermined. Evaluation of the oil provided the analytical assay: 90.5%desired enantiomer by normalized area percent.

EXAMPLE 63-{4(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrileMethod A(3R,4R)-(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0129] 4-Chloropyrrolo[2,3-d]pyrimidine (5.37 grams, 34.9 mmol),prepared by the method of Davoll, J. Am. Chem. Soc., 82, 131 (1960),which is incorporated by reference in its entirety, the product fromExample 2 (6 grams, 27.5 mmol) and potassium carbonate (11.4 grams, 82.5mmol) were combined in water (60 ml). The slurry was heated at refluxfor 90 hrs. The mixture was cooled to 90° C. and toluene (60 ml) wasadded. The biphasic mixture was filtered through filter aid and thelayers were separated. The aqueous layer was extracted with toluene. Thecombined toluene layers were washed with 1N NaOH, treated with activatedcharcoal, and filtered through filter aid. The toluene was evaporated invacuo and the residue crystallized from a 1:1 mixture of isopropylacetate and hexanes to afford 5 grams of an off-white solid; 54% yield.LRMS: 336.1 (M+1).

Method BMethyl-((3R,4R)₄-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0130] To the product from Method A (0.7 grams, 2.19 mmol) dissolved in15 mL of ethanol was added 1.5 mL of 2 N hydrochloric acid and thereaction mixture degassed by nitrogen purge. To the reaction mixture wasthen added 0.5 grams of 20% palladium hydroxide on carbon (50% water)(Aldrich) and the resulting mixture shaken (Parr-Shaker) under a 50 psiatmosphere of hydrogen at room temperature for 2 days. The Celitefiltered reaction mixture was concentrated to dryness in vacuo and theresidue purified by flash chromatography (silica; 5% methanol indichoromethane) affording 0.48 grams (90%) of the title compound. LRMS:246.1 (M+1).

Method C3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile

[0131] To a stirred solution of the product from Method B (1.0 g)dissolved in 30 mL of ethanol was added 0.82 g of cyano-acetic acid2,5-dioxo-pyrrolidin-1-yl ester and the resulting mixture stirred atroom temperature for 2 h. The reaction mixture was filtered throughCelite® and concentrated in vacuo. The residue was redissolved indichloromethane, washed with saturated, aqueous sodium bicarbonate,dried over sodium sulfate, filtered and concentrated to dryness in vacuoaffording 1.1 g (86%) of the title compound as a yellow foam. LRMS: 313(M+1).

EXAMPLE 71-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

[0132] To a stirred solution of the product from Method B (0.03 grams,0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added(0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixturestirred at room temperature for 18 hours. The reaction mixture was thenpartitioned between dichloromethane and saturated sodium bicarbonate(NaHCO₃). The organic layer was washed again with saturated NaHCO₃,dried over sodium sulfate and concentrated to dryness in vacuo. Theresidue was purified by preparative thin layer chromatography (PTLC)(silica; 4% methanol in dichloromethane) affording 0.005 g (15%) of thetitle compound as a colorless oil.

[0133] The title compounds for examples 8-31 were prepared by a methodanalogous to that described in Example 7.

EXAMPLE 8(3R,4R)-[1-(2-Amino-ethanesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 9(3R,4R)-(1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 10(3R,4R)-[1-(Butane-1-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 11(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2.3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid isobutyl ester EXAMPLE 12N-(2-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamideEXAMPLE 13(2-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]Pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-carbamicacid methyl ester EXAMPLE 14N-(2-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-isobutyramideEXAMPLE 15(3R,4R)-(1-Methanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin4-yl)-amine EXAMPLE 16((3R,4R)-1-Ethanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 17(3R,4R)-Methyl-[1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 18(3R,4R)-[1-(Butane-1-sulfonyl)-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 192,2-Dimethyl-N-{(3R,4R)-244-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamideEXAMPLE 20(3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxo-propyl)-carbamicacid tert-butyl ester EXAMPLE 21Methyl-[(3R,4R)-4-methyl-1-(Propane-1-sulfonyl)-piperidin-3-yl]-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-amineEXAMPLE 223-Amino-1-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl-propan-1-oneEXAMPLE 232-Methoxy-1-(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanoneEXAMPLE 242-Dimethylamino-1-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanoneEXAMPLE 25(3-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-carbamicacid tert-butyl ester EXAMPLE 263,3,3-Trifluoro-1-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-oneEXAMPLE 27N-(2-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-acetamideEXAMPLE 283-Ethoxy-1-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-oneEXAMPLE 29(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methylamide EXAMPLE 30(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid diethylamide EXAMPLE 31(3R,4R)-Methyl-[4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

1. A method for resolving enantiomers of a compound containing thestructure of the formula:

pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable base addition salts thereof and free basethereof; wherein y is 0, 1 or 2; R⁴ is selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynylgroups are optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or(C₁-C₆)acylamino; or R⁴ is (C₃-C₁₀)cycloalkyl wherein the cycloalkylgroup is optionally substituted by deuterium, hydroxy, amino,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is (C₂-C₉)heterocycloalkyl wherein theheterocycloalkyl groups must be substituted by one to five carboxy,cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo,(C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; or a group ofthe formula

wherein a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0or 1; d is 0, 1, 2, or 3; X is S(O), wherein n is 0, 1 or 2; oxygen,carbonyl or —C(=N-cyano)-; Y is S(O)_(n) wherein n is 0, 1 or 2; orcarbonyl; and Z is carbonyl, C(O)O—, C(O)NR— or S(O), wherein n is 0, 1or 2; R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(n)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; said methodcomprising the steps of: a) mixing a racemic mixture of enantiomers of acompound, containing the structure of said formula; in a solvent, with aresolving compound having a defined stereospecificity, to form asolution and with said resolving agent being capable of binding with atleast one but not all of said enantiomers to form a precipitate,containing said at least one of said enantiomers, b) allowing themixture to stand for a time sufficient to allow substantialprecipitation of a stereospecific enantiomer of the racemic mixture fromthe solution and wherein another of said enantiomers remains in saidsolution; and c) depending on the stereospecific enantiomer of thecompound which is desired, collecting either the precipitate andpurifying it or collecting the solution with contained other of saidenantiomers and recrystallizing the enantiomer contained in saidsolution.
 2. The method of claim 1, wherein said resolving compound isselected from tartaric acid and its derivatives and adeno acid andderivatives thereof.
 3. The method of claim 2, wherein said tartaricacid derivatives comprise toluoyl and benzoyl tartaric acids instereospecific conformation.
 4. The method of claim 3, wherein thetartaric acid derivative is di-p-toluoyl-L-tartaric acid.
 5. The methodof claim 2, wherein the adeno acid comprises (−) phencyphos.
 6. Themethod of claim 1, wherein the compound is


7. The method of claim 1, wherein the compound is converted to an acidaddition salt form thereof prior to said resolution step.
 8. The methodof claim 7, wherein said addition salt form is a hydrochloride saltform.
 9. The method of claim 1, wherein the temperature at which theresolution and precipitation is effected is ambient temperature and thetime is no more than about four hours.
 10. The method of claim 7,wherein the hydrochloride salt of the compound is formed in a solventselected from the group consisting of methanol, ethanol, isopropanol,acetonitrile, tetrahydrofuran, water, toluene, ethylacetate,dichloromethane, dichloroethane, and mixtures thereof.
 11. The method ofclaim 9, wherein said solvent in which the hydrochloride salt is formedcomprises ethanol with a minor amount of toluene as cosolvent.
 12. Themethod of claim 1, wherein the solvent is selected from the groupconsisting of ethyl acetate, toluene, acetonitrile, heptane, water andmixtures thereof.
 13. The method of claim 1, wherein seeds crystals ofthe precipitating enantiomer are added to facilitate said precipitation.14. A method for preparing the compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R¹ is a groupof the formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is (C₂₋₄-C₉)heterocycloalkyl wherein theheterocycloalkyl groups must be substituted by one to five carboxy,cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo,(C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; or a group ofthe formula II

wherein a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0or 1; d is 0, 1, 2, or 3; X is S(O)_(n) wherein n is 0, 1 or 2; oxygen,carbonyl or —C(=N-cyano)-; Y is S(O)_(n) wherein n is 0, 1 or 2; orcarbonyl; and Z is carbonyl, C(O)O—, C(O)NR— or S(O)_(n) wherein n is 0,1 or 2; R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach independently selected from the group consisting of hydrogen,deuterium, amino, halo, hydoxy, nitro, carboxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl, alkoxy orcycloalkyl groups are optionally substittued by one to three groupsselected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH-(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH-(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl; said method comprising the steps of: a) mixinga racemic mixture of enantiomeric compounds of the formula

wherein y, R⁴ and R⁵ are as defined above, in a solvent, with aresolving compound having a defined stereospecificity, to form asolution and with said resolving agent being capable of binding with atleast one but not all of said enantiomers to form a precipitate,containing said at least one of said enantiomers, b) allowing themixture to stand for a time sufficient to allow substantialprecipitation of a stereospecific enantiomer of the racemic mixture fromthe solution and wherein another of said enantiomers remains in saidsolution; c) depending on the stereospecific enantiomer of the compoundwhich is desired, collecting either the precipitate and purifying it orcollecting the solution with contained other of said enantiomers andrecrystallizing the enantiomer contained in said solution; and d)reacting the desired stereospecific enantiomer so formed with a compoundof the formula

wherein R is hydrogen or a protecting group and R² and R³ are as definedabove.
 15. A compound of the formula

wherein R² and R³ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substittued by one to threegroups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-Cs)heteroaryl,(C₂-Cs)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH-(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl.
 16. A compound according to claim 15, whereinR² and R³ are hydrogen.
 17. A compound selected from the groupconsisting of:Methyl-[(3R,4R)-4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methyl ester;3,3,3-Trifluoro-1-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid dimethylamide;3,3,3-Trifluoro-1-{(3R,4R)-4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;1-{(3R,4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-but-3-yn-1-one;1-{(3R,4R)-3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methylpiperidin-1-yl}-propan-1-one;and1-{(3R,4R)-3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methylpiperidin-1-yl}-propan-1-one.18 (canceled).
 19. A pharmaceutical composition for (a) treating orpreventing a disorder or condition selected from organ transplantrejection, xeno transplation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia andother autoimmune diseases or (b) the inhibition of protein kinases orJanus Kinase 3 (JAK3) in a mammal, including a human, comprising anamount of a compound of claim 15 or 17 or a pharmaceutically acceptablesalt thereof, alone or in combination with one or more additional agentswhich modulate a mammalian immune system or with antiinflammatoryagents, effective in such disorders or conditions and a pharmaceuticallyacceptable carrier. 20-21. (Canceled)
 22. A method for the inhibition ofprotein kinases or Janus Kinase 3 (JAK3) in a mammal, including a human,comprising administering to said mammal an effective amount of acompound of claim 15 or 17 or a pharmaceutically acceptable salt thereofalone or in combination with one or more additional agents whichmodulate a mammalian immune system or with antiinflammatory agents. 23.A method for treating or preventing a disorder or condition selectedfrom organ transplant rejection, xeno transplation, lupus, multiplesclerosis, rheumatoid arthritis, psoriasis, Type I diabetes andcomplications from diabetes, cancer, asthma, atopic dermatitis,autoimmune thyroid disorders, ulcerative colitis, Crohn's disease,Alzheimer's disease, leukemia and other autoimmune diseases in a mammal,including a human, comprising administering to said mammal an amount ofa compound of claim 15 or 17 or a pharmaceutically acceptable saltthereof, alone or in combination with one or more additional agentswhich modulate a mammalian immune system or with antiinflammatoryagents, effective in treating such a condition.
 24. A compound of theformula


25. A compound of the formula


26. (Canceled)